The inspection for and elimination of visible particle contaminated containers from a batch of injectable pharmaceuticals is a United States Pharmacopeia requirement. This inspection is specified to be, whenever possible, after the product is in its final container. Evaluation that the visible particle incidence rate is within USP acceptance limits for human or veterinary use is an essential part of the injectable batch release procedure. It is also an essential prerequisite to the continuous improvement of the quality of an injectable product batch and to the reduction of product cost. These ends have been achieved by incorporating advances in behavioral science, physics and biophysics, illumination and mechanical engineering, pharmaceutics and statistics into a single analytical structure.
Any proposed inspection for visible contaminating particle size in an injectable product, manual semi-automated or fully automated must be validated before it can be used on a United States Pharmacopeia (USP) listed product. Validation in this Good Manufacturing Practices (GMP) sense means that it must be demonstrated to be at least as effective as the preceding method or mechanism. The preceding method of inspecting injectable products for contaminating particles was the inspection of single containers by clinical staff at the injection site.
As shown by one of the authors in several papers, visible contaminating particles are randomly distributed throughout the batch. As such, a validated 100% inspection is essential to achieve accurate, sensitive contaminating particle incidence rate results. The use of the Attribute Sampling Inspection Tables with raw visible particle inspection data results in the incorrect rejection of good batches and incorrect acceptance of undesirable batches. The use of the Knapp-Abramson analysis framework provides the methodology, which transforms raw visible particle inspection data into a form acceptable to the Sampling Tables. For general use, the sensitivity and accuracy of the batch reject rate makes its use more desirable than decisions reached with the model based Sampling Inspection. Although the use of Attribute Sampling Assay Tables can be made compatible with raw visible inspection data, its limited sensitivity and the need to interpret the probability of the results obtained may very well shrink its future use to that of an investigators tool.
The authors of this inventions have been issued several patents in this field of study to aid the in the detection of particles in solutions. U.S. Pat. No. 6,498,645 describes a method for substantially complete detection of all particles, within a predetermined size range, contained in vessel containing an injectable solution. The method measures the blur fringe of particles as they move past the sensor in region near the inner wall of the container.
An improved technology was developed in 2003 the described a unique illumination and optical image system that increased the sensitivity of the detection system, currently the patent is pending (patent application Ser. No. 10/981,801, filed Nov. 5, 2004). The illumination technique and the detector-viewing angle allowed the inventors to examine the complete contents of the container being inspected. The technology allowed the system to identify heavy contaminating particles resting of the bottom of container, something that was not possible using previous technology. The introduction of a visible particle standard set in which the dimensions of the progressively sized single particles are traceable to the primary dimensional standards maintained by NIST makes possible the generation of a calibration curve. This calibration curve relates particle size to particle detectability providing a stable, transportable, national and international reference standard of particle visibility.
The conversion of the prime particle visibility parameter from detection probability to the measurement of particle size results in a measure better suited to continuous monitoring and quality adjustments in a production environment.
Combining NIST traceable sizing of stable microspheres with statistically accurate determinations of their rejection probability has made possible realization of a calibration curve relating the probability of manually detecting a contaminating particle to its NIST traceable maximum physical size. With USP acceptance and use of this calibration curve, inspection sensitivity and discrimination can both be defined and securely evaluated. This means that the basic manual inspection at all producing sites, and therefore the validated capability of any contaminating particle inspection method or mechanism, can now be evaluated on a level playing field. The availability of secure statistically reproducible contaminating particle data makes possible the on-going cycle of parenteral production line process improvements envisioned in Process Analytical Technology (PAT) publications.